Chronic diseases account for over 60% of all deaths worldwide according to the World Health Organization reports. Majority of cases are triggered by environmental exposures that lead to aberrant changes in the epigenome, specifically, the DNA methylation patterns. These changes result in altered expression of gene networks and activity of signalling pathways. Dietary antioxidants, including catechins, flavonoids, anthocyanins, stilbenes and carotenoids, demonstrate benefits in the prevention and/or support of therapy in chronic diseases. This review provides a comprehensive discussion of potential epigenetic mechanisms of antioxidant compounds in reversing altered patterns of DNA methylation in chronic disease. Antioxidants remodel the DNA methylation patterns through multiple mechanisms, including regulation of epigenetic enzymes and chromatin remodelling complexes. These effects can further contribute to antioxidant properties of the compounds. On the other hand, decrease in oxidative stress itself can impact DNA methylation delivering additional link between antioxidant mechanisms and epigenetic effects of the compounds. Linked Articles This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc

Scope Loci‐specific increase in DNA methylation occurs in cancer and may underlie gene silencing. It is investigated whether dietary stilbenoids, resveratrol, and pterostilbene exert time‐dependent effects on DNA methylation patterns and specifically methylation‐silenced tumor suppressor genes in breast cancer cells. Methods and results Following genome‐wide DNA methylation analysis with Illumina‐450K, changes characteristic of early and late response to stilbenoids are identified. Interestingly, often the same genes but at different CpG loci, the same gene families, or the same functional gene categories are affected. CpG loci that lose methylation in exposed cells correspond to genes functionally associated with cancer suppression. There is a group of genes, including SEMA3A, at which the magnitude of hypomethylation in response to stilbenoids rises with increasing invasive potential of cancer cells. Decreased DNA methylation at SEMA3A promoter and concomitant gene upregulation coincide with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids may be linked to decreased DNMT3A binding followed by increased NF1C transcription factor occupancy. Sequestration of DNMT3A is possibly a result of stilbenoid‐mediated increase in SALL3 expression, which was previously shown to bind and inhibit DNMT3A activity. Conclusions The findings define mechanistic players in stilbenoid‐mediated epigenetic reactivation of genes suppressing cancer.

triple-negative breast cancer (tnBc) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths. invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DciS). Detection of triple-negative DciS (tn-DciS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive tn-DciS to invasive tnBc are needed. Here, we study a canine tn-DciS progression and investigate the DnA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DciS and invasive breast cancer. We report hypo-and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DnA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DciS. changes in DnA methylation during tn-DciS progression in this canine model correspond with gene expression patterns in human breast tissues. this study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DciS stage only of tn-DciS progression. Breast cancer is classified into subtypes based on the expression of growth factor receptors including the estrogen receptor (ER), the progesterone receptor (PR), and the receptor for human epidermal growth factor (HER-2) 1. Growth of breast tumors expressing any of these receptors may be controlled effectively by treatment in the adjuvant setting with receptor-targeted drugs 2. However, breast tumors that do not express any of these receptors have no known effective adjuvant treatment capable of controlling tumor growth. Such tumors are referred to as triple-negative breast cancers (TNBC) and are the most aggressive and lethal of all breast malignancies 2. TNBC accounts for 15% of breast cancer cases and a disproportionate percentage of breast cancer deaths among women 3. It has been shown that patients with TNBC have poor prognosis and shorter median time to relapse compared to patients with other subtypes of breast cancer 4. Ductal carcinoma in situ (DCIS) is defined as a non-invasive overgrowth of cells characterized by high proliferation within the breast ductal system. Studies suggest that triple-negative DCIS (TN-DCIS), a rare type of DCIS, is a precursor stage of invasive breast cancer 5,6. Therefore, early detection of TN-DCIS is important in preventing breast cancer cases that may progress to triple negative invasive carcinoma. However, TN-DCIS is challenging to detect at early stage in humans 7. Despite efforts to use immunohistochemistry to measure receptor expression in scientific studies of human DCIS tissues, detection of receptor status, including ER, is not routi...

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Epigenetic aberrations are linked to sporadic breast cancer. Interestingly, certain dietary polyphenols with anti-cancer effects, such as pterostilbene (PTS), have been shown to regulate gene expression by altering epigenetic patterns. Our group has proposed the involvement of DNA methylation and DNA methyltransferase 3B (DNMT3B) as vital players in PTS-mediated suppression of candidate oncogenes and suggested a role of enhancers as target regions. In the present study, we assess a genome-wide impact of PTS on epigenetic marks at enhancers in highly invasive MCF10CA1a breast cancer cells. Following chromatin immunoprecipitation (ChIP)-sequencing in MCF10CA1a cells treated with 7 μM PTS for 9 days, we discovered that PTS leads to increased binding of DNMT3B at enhancers of 77 genes, and 17 of those genes display an overlapping decrease in the occupancy of trimethylation at lysine 36 of histone 3 (H3K36me3), a mark of active enhancers. We selected two genes, PITPNC1 and LINC00910, and found that their enhancers are hypermethylated in response to PTS. These changes coincided with the downregulation of gene expression. Of importance, we showed that 6 out of 17 target enhancers, including PITPNC1 and LINC00910, are bound by an oncogenic transcription factor OCT1 in MCF10CA1a cells. Indeed, the six enhancers corresponded to genes with established or putative cancer-driving functions. PTS led to a decrease in OCT1 binding at those enhancers, and OCT1 depletion resulted in PITPNC1 and LINC00910 downregulation, further demonstrating a role for OCT1 in transcriptional regulation. Our findings provide novel evidence for the epigenetic regulation of enhancer regions by dietary polyphenols in breast cancer cells.